Cutaneous leishmaniasis responds to daylight-activated photodynamic therapy: proof of concept for a novel self-administered therapeutic modality.

BACKGROUND: Cutaneous leishmaniasis (CL) is endemic in Israel, with hundreds of new cases reported in recent years. Photodynamic therapy (PDT) is highly effective for treatment of CL, but requires equipment available only at specialized centres. Daylight-activated PDT (DA-PDT) abolishes the need for artificial light sources and allows the patient to administer the treatment with no professional assistance. OBJECTIVES: The objective of this single-centre, open study was to establish proof of concept for the efficacy of DA-PDT in the treatment of CL using clinical, microbiological and molecular clearance as outcome measures. METHODS: Thirty-one patients with CL (11 Leishmania major and 20 Leishmania tropica) underwent DA-PDT. Fourteen patients were treated in the hospital garden under professional supervision and 17 patients underwent DA-PDT as a self-administered treatment modality at home. Following application of a thick layer of 16% methyl aminolaevulinate and 30-min occlusion, the lesions were exposed to daylight for 2·5 h. Treatment sessions were repeated at weekly intervals until clinical and microbiological cure. Control lesions were either treated with cryotherapy or left untreated. RESULTS: The overall cure rate for DA-PDT was 89% (intention-to-treat cure rate 77%); this was 86% for the hospital-based treatment group and 92% for the self-administered group. CONCLUSIONS: DA-PDT proved to be effective in the treatment of CL caused by L. major and L. tropica. More patients were treated according to a self-administered protocol, suggesting that DA-PDT can be adopted even in technologically deprived countries where the majority of Leishmania infections are encountered.

Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial.

BACKGROUND: Daylight photodynamic therapy (DL-PDT) of actinic keratosis (AK) has shown preliminary efficacy and safety results comparable to conventional photodynamic therapy (c-PDT), using methyl aminolevulinate (MAL) cream. OBJECTIVES: To demonstrate the efficacy and safety of DL-PDT vs. c-PDT in treating mild facial/scalp AK. MATERIALS AND METHODS: This 24-week randomized, controlled, investigator-blinded, multicentre, intra-individual efficacy (non-inferiority) and safety (superiority regarding pain) study enrolled 100 subjects. AKs on the face/scalp were treated once, with DL-PDT on one side and c-PDT on the contralateral side. Primary end points for DL-PDT at week 12 were efficacy [non-inferiority regarding complete lesion response (mild AK)] and safety (superiority regarding subject's assessment of pain). Lesions with complete response 12 weeks after one treatment session were followed until week 24. The safety evaluation included incidence of adverse events. Subject satisfaction was classified using a questionnaire. RESULTS: At week 12, the complete lesion response rate with DL-PDT was non-inferior to c-PDT (89·2% vs. 92·8%, respectively; 95% confidence interval -6·8 to -0·3), confirmed by intention-to-treat analysis. Additionally, regardless of the treatment used, 96% of mild lesions were maintained in complete response 24 weeks after the PDT session. For DL-PDT, subject-reported pain was significantly lower (0·8 vs. 5·7, respectively; P < 0·001), with better tolerability and significantly higher subject satisfaction regarding convenience and outcome. CONCLUSIONS: Daylight-mediated PDT was not inferior in efficacy to Metvix c-PDT (mild AK response rate), better tolerated, nearly painless and more convenient for patients.

A randomized, multicentre study of directed daylight exposure times of 1½ vs. 2½ h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp.

BACKGROUND: Actinic keratoses (AKs) are common dysplastic skin lesions that may differentiate into invasive squamous cell carcinomas. Although a superior cosmetic outcome of photodynamic therapy (PDT) is advantageous compared with equally effective treatments such as cryotherapy and curettage, the inconvenience of clinic attendance and discomfort during therapy are significant drawbacks. Daylight-mediated PDT could potentially reduce these and may serve as an alternative to conventional PDT. OBJECTIVES: To compare the efficacy of methyl aminolaevulinate (MAL)-PDT with 1½ vs. 2½ h of daylight exposure in a randomized multicentre study. METHODS: One hundred and twenty patients with a total of 1572 thin AKs of the face and scalp were randomized to either 1½- or 2½-h exposure groups. After gentle lesion preparation and application of a sunscreen of sun protection factor 20, MAL was applied to the entire treatment area. Immediately after, patients left the clinic and exposed themselves to daylight according to the randomization. Daylight exposure was monitored with a wristwatch dosimeter and patients scored their pain sensation during treatment. RESULTS: The mean lesion response rate at 3 months was 77% in the 1½-h group and 75% in the 2½-h group (P = 0·57). The mean duration of daylight exposure was 131 and 187 min in the two groups. The mean overall effective light dose was 9·4 J cm(-2) (range 0·2-28·3). Response rate was not associated with effective daylight dose, exposure duration, treatment centre, time of day or time of year during which the treatment was performed. Treatment was well tolerated, with a mean ± SD maximal pain score of 1·3 ± 1·5. CONCLUSIONS: Daylight-mediated MAL-PDT is an effective, convenient and nearly pain-free treatment for patients with multiple thin AKs. Daylight-mediated PDT procedures were easily performed and 2 h of daylight exposure resulted in uniformly high response rates when conducted in the period from June to October in Nordic countries.

Photodynamic therapy of actinic keratoses with 8% and 16% methyl aminolaevulinate and home-based daylight exposure: a double-blinded randomized clinical trial.

BACKGROUND: Photodynamic therapy (PDT) is an effective but time-consuming and often painful treatment for actinic keratosis (AK). Home-based daylight-PDT has the potential to facilitate treatment procedure and to reduce associated pain due to continuous activation of small amounts of porphyrins. Moreover, a reduced methyl aminolaevulinate (MAL) concentration may reduce associated inflammation, making the treatment more tolerable for the patients. OBJECTIVES: To compare response rates and adverse effects after PDT using conventional 16% and 8% MAL with home-based daylight exposure in treatment of AK. METHODS: Thirty patients with mostly thin-grade AK of the face or scalp were treated with 16% and 8% MAL-PDT in two symmetrical areas after application of sunscreen. Immediately after, patients left the hospital with instructions to spend the remaining day outside at home in daylight. Patients scored pain during treatment and light exposure was monitored with an electronic wristwatch dosimeter. RESULTS: The complete response rate after 3 months was 76.9% for 16% MAL and 79.5% for 8% MAL (P = 0.37). Patients spent a mean of 244 min outdoors and received a mean effective light dose of 30 J cm(-2). Light doses of 8-70 J cm(-2) induced similar response rates (P = 0.25). Patients experienced mild to moderate pain during daylight exposure (mean maximal pain score of 3.7). No differences in pain scores and erythema were seen between the areas treated with 16% MAL and with 8% MAL. CONCLUSIONS: Home-based daylight-mediated MAL-PDT was an effective and well-tolerated treatment for AK. No differences in response rates or adverse events were found between the areas treated with 16% MAL and with 8% MAL.

Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study.

BACKGROUND: Photodynamic therapy (PDT) is a highly effective treatment for actinic keratoses (AK); however, it is time consuming and often painful for the patient. Daylight-PDT would make the treatment independent of the clinic and less painful due to the continuous activation of small amounts of porphyrins during its formation. OBJECTIVES: The objective of this randomized controlled study was to compare response rates and adverse effects after methyl aminolevulinate (MAL)-PDT using conventional red light-emitting diode (LED) light vs. daylight. PATIENTS/METHODS: Twenty-nine patients with AK of the face and scalp were treated with MAL-PDT in two symmetrical areas. One area was illuminated by red LED light (37 J cm(-2)) after 3-h incubation with MAL under occlusive dressing. The other area was treated with daylight for 2.5 h after the MAL cream had been under occlusion for half an hour. RESULTS: We found no significant difference in the treatment effect between the two treatments (P = 0.13), with a reduction of AK lesions of 79% in the daylight area compared with 71% in the LED area. Treatment response in the daylight area did not depend on the intensity of the daylight. Illumination with LED was more painful than daylight (P < 0.0001). Erythema and crusting occurred after both treatments and were similar in the two areas. CONCLUSIONS: PDT of AK by continuous activation of porphyrins by daylight proved to be as effective as conventional PDT. PDT using daylight activation will make the treatment of these extremely common premalignant tumours more time and cost effective, and more convenient for the patient.

Evidence-based review of hair removal using lasers and light sources.

BACKGROUND: Unwanted hair growth remains a therapeutic challenge and there is a considerable need for an effective and safe treatment modality. OBJECTIVE: From an evidence-based view to summarize efficacy and adverse effects from hair removal with ruby, alexandrite, diode, and Nd:YAG lasers and intense pulsed light (IPL). METHODS: Original publications of controlled clinical trials were identified in Medline and the Cochrane Library. RESULTS: A total of 9 randomized controlled (RCTs) and 21 controlled trials (CTs) were identified. The best available evidence was found for the alexandrite (three RCTs, eight CTs) and diode (three RCTs, four CTs) lasers, followed by the ruby (two RCTs, six CTs) and Nd:YAG (two RCTs, four CTs) lasers, whereas limited evidence was available for IPL sources (one RCT, one CT). Based on the present best available evidence we conclude that (i) epilation with lasers and light sources induces a partial short-term hair reduction up to 6 months postoperatively, (ii) efficacy is improved when repeated treatments are given, (iii) efficacy is superior to conventional treatments (shaving, wax epilation, electrolysis), (iv) evidence exists for a partial long-term hair removal efficacy beyond 6 months postoperatively after repetitive treatments with alexandrite and diode lasers and probably after treatment with ruby and Nd:YAG lasers, whereas evidence is lacking for long-term hair removal after IPL treatment, (v) today there is no evidence for a complete and persistent hair removal efficacy, (vi) the occurrence of postoperative side-effects is reported low for all the laser systems. CONCLUSION: The evidence from controlled clinical trials favours the use of lasers and light sources for removal of unwanted hair. We recommend that patients are pre-operatively informed of the expected treatment outcome.

Minimal erythema dose after multiple UV exposures depends on pre-exposure skin pigmentation.

BACKGROUND/PURPOSE: Phototherapy consists of multiple ultraviolet (UV) exposures. Most previous studies have focused on erythema following a single UV exposure in fair-skinned persons. Although it is well known that phototherapy lowers the daily UV-threshold dose for erythema in clinical practice, this is insufficiently documented under controlled experimental conditions. The purpose of this study was to quantify the change in the daily threshold for a dose specific erythema grade after 1-4 consecutive daily UV exposures. METHODS: Forty-nine healthy volunteers (skin type II-V) with varying pigmentation quantified by skin reflectance. Two UV sources were used: a narrowband UVB (Philips TL01) and a Solar Simulator (Solar Light Co.). Just perceptible erythema after 24 h was chosen as the minimal erythema dose (+); besides + and ++ were assessed. RESULTS: We found a positive and significant exponential relationship between skin pigmentation and UV dose to elicit a specific erythema grade on the back after 1-4 UV exposures. After repetitive UV exposures the UV dose had to be lowered more in dark-skinned persons compared with fair-skinned persons to elicit a certain erythema grade. This applied to both UV sources and all erythema grades. CONCLUSION: In the dark-skinned persons the daily UV dose after the 4 days UV exposure should be lowered by 40-50% to avoid burns compared with the single UV exposure. For the most fair-skinned persons essentially no reduction in the daily UV dose was needed. Our results indicate that the pre-exposure pigmentation level can guide the UV dosage in phototherapy.

A UVB phototherapy protocol with very low dose increments as a treatment of atopic dermatitis.

From 1991 to 1992, 15 patients with atopic dermatitis were treated with a new UVB treatment regimen guided by skin reflectance measurements. The new treatment was characterized by very low dose increments from start to end of therapy. The median cumulative dose increment during therapy was only 20%. The severity of the disease, the efficacy of the treatment, the occurrence of adverse effects and the cumulative UVB dose were obtained from the case records. This data were compared in an open study with the data obtained from 17 patients with atopic dermatitis who were treated from 1988 to 1991 at the department with a standard UVB treatment regimen with stepwise dose increments. There was no difference in the severity of the disease at the beginning of the therapy between the two groups. The skin reflectance-guided low-dose UVB therapy was not significantly faster (3.5 weeks) than the regimen with stepwise dose increments (4.5 weeks). The cumulative UV exposure was four times lower with the new treatment regimen (34 standard erythema doses) compared with the old regimen (161 standard erythema doses), P<0.001. The healing score was significantly higher with the new treatment regimen compared with the old, P<0.05. This study indicates that skin reflectance-guided UVB phototherapy may enable the dermatologist to lower the cumulative UVB exposure significantly without losing effect.

Sun exposure and sunscreen use among sunbathers in Denmark.

Eight hundred and eight sunbathing Danes were interviewed in order to register the duration of sun exposure and sunscreen use. The mean sun exposure time, 203 min, was found to be independent of sex, age and use of sunscreen. Overall, sunscreens were used by 65%, 73% of the females and 52% of the males. The median sun protection factor used by subjects older than 10 years was 5; in the case of children 10 years or younger, it was 12. Eight per cent of the interviewed subjects used more than one factor. Fifty-seven per cent of the sunscreen users applied the sunscreen prior to arriving at the beach. The sun exposure time was not significantly different in the group of subjects using sunscreens, compared to the group of subjects not using sunscreens. This study indicates that sunscreen users may not increase their exposure to the sun.

Photoprotection due to pigmentation and epidermal thickness after repeated exposure to ultraviolet light and psoralen plus ultraviolet A therapy.

Tanning and thickening of the epidermis are cardinal defensive responses of human skin to ultraviolet (UV) radiation that lead to increased photoprotection. Earlier studies have shown that skin pigmentation can be used to predict minimal erythema dose and minimal phototoxic dose. In this study it was calculated how much of the increase in photoprotection after 4 weeks of repeated exposure to suberythemogenic doses of either UVA or UVB radiation sources or psoralen plus UVA (PUVA) therapy that was attributable to melanogenesis. The backs of 12 volunteers were exposed to 6 different UVA and UVB radiation sources 9 times during 4 weeks. Skin pigmentation was assessed by skin reflectance measuring. Photoprotection was determined from the minimal erythema dose. Melanogenesis accounted for 63-95% of the increase in photoprotection after 4 weeks of exposure to UVA radiation. Exposure to two UVB sources induced a significant increase in photoprotection but not in pigmentation. Melanogenesis accounted only for 6-11% of the increase in photoprotection after 4 weeks of UVB exposure. The pigmentary and photoprotective responses to PUVA therapy were followed in 14 patients. After 2 weeks of exposure, the increase in photoprotection was significantly higher than predicted from the increase in skin pigmentation. After 4 weeks, melanogenesis accounted for only 36% of the increase in photoprotection. This study shows that melanogenesis accounts for the increased photoprotection after 2 weeks of exposure to UVA radiation, but after 4 weeks other protective mechanisms occur. During suberythemal UVB exposure and during PUVA therapy the importance of skin pigmentation in the overall photoprotection gradually decreases during a 4-week irradiation period.

8-methoxypsoralen increases daytime plasma melatonin levels in humans through inhibition of metabolism.

It is well established that in healthy humans oral intake of 5- or 8-methoxypsoralen (5- and 8-MOP) is followed by a significant increase in plasma melatonin concentrations. The effect of psoralen on rat melatonin has been studied in vitro and in vivo and a stimulation of release or secretion from the pineal gland has been suggested. In this study we examined the time-related changes in plasma concentrations of 8-MOP, melatonin and 6-sulfatoxymelatonin in 15 patients admitted for routine psoralen plus UVA therapy. On the first day of treatment blood samples were collected before, and 30, 60, 66 and 90 min after intake of 8-MOP (0.6 mg/kg). Although the rate of 8-MOP absorption varied greatly, a significant increase (P = 0.0002) in melatonin levels was found 60 min after 8-MOP intake. During UVA exposure a strongly correlated decrease in mean melatonin and mean 8-MOP concentrations was found, indicating an effect of UVA radiation, either direct or 8-MOP mediated, on circulating melatonin levels. Plasma 6-sulfatoxymelatonin concentrations decreased significantly between all time points, suggesting inhibition of melatonin metabolism.

Skin pigmentation as a predictor of minimal phototoxic dose after oral methoxsalen.

BACKGROUND AND DESIGN: Twenty-eight subjects were phototested to determine their erythemal responses to oral methoxsalen with UV-A and UV-B irradiation. Skin pigmentation was measured by skin reflectance at 550 and 660 nm before irradiation. The smallest UV radiation dose to produce erythema (minimal phototoxic dose and minimal erythema dose, respectively) was determined. The serum concentration of methoxsalen was measured at the time of UV-A irradiation. RESULTS: There was a positive correlation between skin pigmentation and both 72-hour minimal phototoxic dose and 24-hour minimal erythema dose. No correlation was demonstrated between methoxsalen serum concentration and minimal phototoxic dose. The combination of skin pigmentation and methoxsalen level did not give a better prediction of minimal phototoxic dose than skin pigmentation alone. CONCLUSIONS: Skin pigmentation measurements can be used to predict the minimal phototoxic and erythema doses. Skin pigmentation measurements are easy to perform and should be included in both phototherapy and photochemotherapy to improve the efficiency and reliability of the treatment.

Erythema after irradiation with ultraviolet B from Philips TL12 and TL01 tubes.

A trial was conducted to investigate whether the experimentally found erythema caused by irradiation from Philips TL12 (TL12) and Philips TL01 (TL01) tubes corresponded to the expected erythema efficacy calculated from the CIE erythema action spectrum. Using the CIE erythema action spectrum and the emission spectra of the two tubes, the ratio between the calculated erythema efficacy of the two tubes is TL12:TL01 = 1:4.2. Seventeen volunteers were irradiated on previously unexposed buttocks with TL12 and TL01 in doses ranging from 0.8 to 3.3 kJ/m2 and from 3.1 to 18.6 kJ/m2 respectively. The erythema was evaluated clinically and measured by skin reflectance before and 24 h after exposure. Also the pigmentation of the skin was measured before exposure. The erythema efficacy ratio between TL12 and TL01 was found to be 1:2.8. This indicates that TL01 is more or TL12 is less potent than should be expected from the CIE erythema action spectrum and that this should be taken into account when changing from TL12 to TL01 in therapy.

Sunbathers' application of sunscreen is probably inadequate to obtain the sun protection factor assigned to the preparation.

The sun protection factor (SPF) is a ratio that estimates the protective efficacy of a sunscreen against sunburn. The generally accepted methods used to determine the SPF of a sunscreen require that the formulation be applied in a thickness of 1.5 mg/cm2 (Deutsches Institut für Normung) or 2 mg/cm2 (US Food and Drug Administration). The applied thickness of a sunscreen is important for the degree of photoprotection. Forty-two volunteers on a beach applied their own sunscreen all over the body. The amount of the applied sunscreen was on average 0.5 mg/cm2. This indicates that the labelled SPF is probably considerably higher than the obtained degree of protection against sunburn.

Selenium and its interrelation with mercury in wholeblood and hair in an East Greenlandic population.

138 Blood samples and 12 hair samples from the district of Angmagssalik, East Greenland, have been analysed for selenium and mercury. It was found that selenium like mercury, was absorbed in accordance with the amount of marine food eaten. The mean blood concentration in the group eating most marine food was 173 and 186 micrograms Hg/1 for men and women, respectively, while in the group eating the lowest quantity of marine food, the mean values were 86 and 118 micrograms Hg/1. In blood, the selenium and mercury did not correlate in individuals, but only in groups according to eating habits. On a molar basis, selenium is present in blood in excess as compared to mercury, while the opposite is the case for hair. It is concluded that only part of the selenium interacts with mercury, and that blood, but not hair, reflects present dietary intake. The righ supply of selenium in relation to mercury exposure through the traditional arctic food is probably able to alleviate the hazards from dietary mercury exposure.

Carcinogenic effect of sequential artificial sunlight and UV-A irradiation in hairless mice. Consequences for solarium 'therapy'.

The carcinogenic effect of artificial UV sunlight followed by UV-A irradiation in human solaria doses has been studied with the use of the hairless mouse as an animal model. Artificial sunlight exposure alone induced only a moderate skin tumor incidence (animals with at least one tumor) of 0.15 after one year, and UV-A irradiation alone induced no tumor formation. However, the combination of artificial sunlight exposure and subsequent UV-A irradiation significantly increased the tumor incidence to 0.72. We conclude that, in humans, tanning with UV-A for cosmetic purposes may not be an innocuous procedure.